Comparison of Commercially Available Reagents for Fluorination of Steroid 3,5-Dienol Acetates

Abstract

Reactions of steroid 3,5-dienol acetates with electrophilic fluorinating reagents of the N-fluoro quaternary salt class were examined for the purpose of selecting a reagent for use in commercial scale synthesis. The neutral N-fluorosulfonimides gave high β-fluoro selectivity and moderate yields. In the N-fluoropyridinium class, high temperatures or long reaction times required for complete reaction led to low yields. The change in selectivity of fluorination reported at different temperatuers with N-fluoropyridinium pyridine heptafluorodiborate (NFPy) was explained by selective dehydrohalogenation of the β-fluoro isomer to the 3-keto 4,6-diene product. With 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) the elimination was slowed. Additionally, Selectfluor was observed to react with the unactivated double bond in Δ9(11) steroids to give 11α-fluoro-9β-methyl phenols. Selectfluor was chosen as the optimum reagent, and a process was developed using that reagent. Epimerizations of 6α/β-fluoro steroid mixtures to pure 6α-fluoro steroids were also examined, and conditions for preparation of pure 6α-fluoro steroids were developed.